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Complement

General paediatrics, Immunology, Infectious disease

C3 and C4 are measured at the same time since this gives an indication of the complement pathway (classical or alternative) which is being activated and thus the cause of this activation.

C3 alone is often decreased in infectious disease (septicaemia, endocarditis), so not v interesting if isolated, unless concern about immunodeficiency (see below).

C4 alone is characteristically decreased in hereditary angioedema, can also be immune complex diseases particularly vasculitis, and in cryoglobulinaemia and cold agglutinin disease. Immune complex diseases can lead to consumption of both C3 and C4, with low levels.

Measurement of serum complement is useful in the monitoring of specific immune complex diseases eg SLE, post streptococcal disease, subacute bacterial endocarditis. Consumption of one or both components may also be useful prognostically eg nephritis in lupus.

Deficiency

Complement deficiency is a type of immunodeficiency.  Though genetic C3 deficiency is v rare, deficiencies in other components (which are more common, though still very rare) can result in low C3.  CH50 or CH100 are better tests of whole pathway.

Genetic deficiencies in C4 are rarely detected.

Notifiable diseases (Scotland)

General paediatrics, Infectious disease, Microbiology

Public Health etc Act Scotland 2008

There are notifiable diseases and notifiable organisms:

Notifiable diseases

  • Clinical syndrome due to E.coli O157 infection
  • Haemolytic Uraemic Syndrome (HUS)
  • Necrotizing fasciitis
  • Severe Acute Respiratory Syndrome (SARS)
  • (plus infections caused by organisms below)

Notifiable organisms

  • Bacillus anthracis (anthrax)
  • Bacillus cereus
  • Bordetella pertussis
  • Borrelia burgdorferi (Lyme disease)
  • Brucella genus
  • Campylobacter genus
  • Chlamydia psittaci
  • Clostridium botulinum (Botulism)
  • Clostridium difficile
  • Clostridium perfringens
  • Clostridium tetani
  • Corynebacterium diphtheriae (toxigenic strains)
  • Corynebacterium ulcerans
  • Coxiella burnetii
  • Crimean-Congo haemorrhagic fever virus
  • Cryptosporidium
  • Dengue virus
  • Ebola virus
  • Echinococcus genus
  • Verocytotoxin-producing E.coli (VTEC)
  • Francisella tularensis
  • Giardia lamblia
  • Guanarito virus
  • Haemophilus influenzae type b (from blood, cerebrospinal fluid or other normally sterile site)
  • Hantavirus
  • Hepatitis A-E virus
  • Influenza virus (all types, including those caused by a new sub-type)
  • Junín virus
  • Kyasanur Forest disease virus
  • Lassa virus
  • Legionella genus
  • Leptospira genus
  • Listeria monocytogenes
  • Machupo virus
  • Marburg virus
  • Measles virus
  • Mumps virus
  • Mycobacterium bovis
  • Mycobacterium tuberculosis complex
  • Neisseria meningitidis
  • Norovirus
  • Omsk haemorrhagic fever virus
  • Plasmodium falciparum, vivax, ovale and malariae (malaria)
  • Polio virus
  • Rabies virus
  • Rickettsia prowazekii
  • Rift Valley fever virus
  • Rubella virus
  • Sabia virus
  • Salmonella (all human types)
  • SARS-associated coronavirus
  • Shigella genus
  • Enterotoxigenic Staphylococcus aureus
  • Staphylococcus aureus (all blood isolates)
  • Methicillin-resistant Staphylococcus aureus (MRSA)
  • Streptococcus pyogenes (from blood, cerebrospinal fluid or other normally sterile site)
  • Streptococcus pneumoniae (from blood, cerebrospinal fluid or other normally sterile site)
  • Toxoplasma gondii
  • Trichinella genus
  • Varicella-zoster virus
  • Variola virus
  • Vibrio cholerae
  • West Nile fever virus
  • Yellow Fever virus
  • Yersinia enterocolitica
  • Yersinia pestis
  • Yersinia pseudotuberculosis

Polycystic ovary syndrome (PCOS)

Endocrinology, General paediatrics, OPD

No single test. Polycystic kidneys are a common incidental finding at USS, so not sufficient for diagnosis.  Also operator dependent esp teens.

  • Hirsutism (even male pattern baldness), But NOT virilisation (eg clitoromegaly, voice changes, musculature).
  • acne (moderate to severe),
  • irregular periods.  Can be amenorrhoeic, dysfunctional uterine bleeding, infertility but 20% have normal cycle.
  • Obesity (35-50%, not all),
  • Acanthosis nigricans.

Insulin resistance is associated, and obviously presents the most important long term risk. Acanthosis nigricans is highly associated with insulin resistance, family history of type 2 or gestational diabetes a clue.

Differential includes pregnancy, hypothyroidism, hyperprolactinaemia (mild hyperprolactinaemia commonly seen in PCOS, transient), late onset Congenital Adrenal Hyperplasia (CAH), ovarian/adrenal tumour, Cushing syndrome.

Investigations

  • LH/FSH – ratio often high (3:1 or more) but inconsistent so not considered diagnostic
  • Testosterone can be high (up to 4.8) – if higher, suggests alternative diagnosis
  • Free androgen index (=testosterone x100/SHBG) can be high but our lab only calculates for adults – reference range of up to 7
  • SHBG – low in PCOS (and in obesity, hypothyroidism, hyperprolactinaemia). Plus marker of insulin resistance),
  • Prolactin, 17OH Progesterone for differential
  • Fasting glucose/insulin ratio (under 4.5=insulin resistance, up to 7 in adolescents), glucose tolerance test, lipids.

Manage symptoms (for young people hirsutism, adults infertility) and long term risk viz diabetes and cardiovascular disease.

Note that less than 4 menses per year has higher risk of endometrial cancer.

Consider:

  • oral contraceptive pill (OCP) – progesterone only, or combined, or else 12 week cycles of medroxyprogesterone acetate 5mg BD followed by 1 week break – NOT contraceptive!
  • Metformin
  • Spironolactone (has anti androgen effect)
  • Plucking/shaving/electrolysis/laser, eflornithine cream
  • Clomiphene for fertility.

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1069067/]

Congenital Syphilis

Congenital, General paediatrics, Infectious disease, Microbiology, Neonatology

In US primary, secondary and cong syphilis all surged in the 90s, now focal outbreaks in urban, drug using population. In N Africa, 3% of pregnancies, up to 7% in Carribean. 1 million pregnancies affected worldwide, of which 50% will end in abortion or still birth, and the other 50% will be congenital cases (unlike TORCH).

Clinically, 2/3 affected neonates asymptomatic at birth. Otherwise:

  • “snuffles” (vesicles on upper lip, highly infectious)
  • mucous patches (moist erosions)
  • hepatosplenomegaly and hepatitis
  • anaemia +/- hydrops
  • meningitis, with CSF pleocytosis and high protein
  • pneumonia, +/or fluffy diffuse infitrates on CXR (=pneumonia alba)
  • pseudoparalysis

Years later:

  • Typical facies – frontal bossing, saddle nose, short maxilla, high palate
  • Mulberry Molar (5 blobs in ring shape to tooth, pathognomic!). Hutchinson’s incisors (peg-like) better known.
  • Gummata (rubbery ulcers)
  • Sabre tibia (anterior bowing)
  • Hutchinson’s triad = interstitial keratitis, peg shaped incisors, and sensorineural deafness.

Prevention

The risk of transmission is very high, particularly for untreated primary (ie a chancre) or secondary (ie multiple lesions, lymphadenopathy) disease. The risk falls to 40% for early latent syphilis (ie test positive but asymptomatic, with infection likely to have occurred in the previous 12 months on the basis of previous tests, symptoms or exposure). A category exists of latent syphilis of unknown duration, which only applies to patients aged 13-35yrs with nontreponemal titre of 32 or more.

Treating syphilis in pregnancy – for early acquired disease (primary, secondary or latent of <1yr) benzathine penicillin 50 000U/kg, with second dose a week later if in third trimester [BNF] but exclude neuro. For late latent syphilis >1yr duration give 3 doses at weekly intervals. For neuro disease benzylpen 50 000U/kg qds for 10-14/7 followed by 3 doses benzathine penicillin as above. If HIV positive also, then there tends to be more CNS disease, treatment failure, and treatment reactions (fever, myalgia, preterm labour – give steroids).

Adequate antenatal treatment = adequate benzathinepenicillin dose (2.4M Units IM) once weekly x3 – erythromycin is not reliable), 30 days before birth, proven 4x drop in nontreponemal serology.

Diagnosis

Syphilis tests are either nontreponemal or treponemal.

  • Nontreponemal viz VDRL, RPR are screening tests, 70% sensitive in primary, 99% in secondary.
    • False positives – lupus, infection, recent immunization, pregnancy, other treponemes.
    • Quantitative – correlate with disease activity: 4x rise in titre early on or in relapse, drop of 4x suggests adequate response to treatment. In secondary, titres are always high ie 1:32.
    • False negative – early? Tertiary – V high levels of antibody! So if high suspicion then do dilutions.
    • Should become negative within 1 yr of treatment in primary, 2 yrs in secondary or congenital, 5 yrs in late.
  • Specific treponemal tests eg TP immobilization (TBI), fluorescent T antibody absorption (FTA-Abs) used to confirm.
    • False positive with non pallidum, Lyme or other borrelia.
    • Remain positive for life, even with treatment.
    • Do not correlate with disease activity.
    • FTA-Abs IgM available for testing baby, but still has false positives/negatives

In newborns, direct microscopy and fluorescent antibody tests can be done from mucous patch, else from placenta (beware non pallidum treponemes in normal flora esp mouth). PCR can be done from lesions too. VDRL more than 2x dilutions richer than mum’s is suggestive. IgM can be negative early esp infection occurring late in pregnancy, not always recommended. False positive VDRL may occur due to transplacental antibodies if high maternal levels.

Where disease is likely, or maternal treatment has been inadequate, further testing is required:

  • FBC, LFTs
  • Lumbar puncture, incl VDRL on CSF (not 100% sensitive so if congenital disease suspected, treat for neuro.)
  • XR long bones to look for destructive lesions. Even in asymptomatic, XR changes seen in 20% esp ankles, knees but also wrists, elbows. Lesions are symmetric, multiple: periostitis, osteitis, osteochondritis.
  • CXR
  • Ophthalmology assessment

For screening adults, 1 step strip test available, and one off oral treatment (Azithro, 1.8g). Antibodies give only partial protection.

Treatment

For congenital syphilis treat with benzylpen 100-150 000 U/kg/d in bd or tds doses for 10-14/7.

There is concern about CSF levels with procaine or benzathine penicillin, although sometimes these are used for asymptomatic babies with nontreponemal tests less than 4x mum’s, which might occur with inadequate treatment. In this situation, any abnormal finding on evaluation requires full 10/7 course.

If late diagnosis (>4/52), give high dose viz 200-300 000 U/kg/d qds for 10-14/7. If CNS disease is excluded, this could be converted to benzathine penicillin.

Follow up

Monitor to show fall in VDRL at 3-6 months.

(Rana Chakraborty, St George’s)

Bawa Garba case

Clinical governance, Ethics, Generic

High Court ruling regarding Dr Hadiza Bawa-Garba following the tragic death of a 6-year-old boy in 2011. Subsequently convicted of manslaughter. Removed from the GMC register, although Medical Practitioners Tribunal Service (MPTS) decision was to suspend for a year.  GMC appealed, saying it had not taken into account the manslaughter conviction.

High Court then overturned erasure, saying that tribunal did not commit any errors in its procedures, and therefore its conclusions were valid.

The trust acknowledged systemic failures, so why the vindictiveness? Its report into the death (“no single error responsible for death”) was not brought before jury, as being beyond scope of the trial! Not lazy or under influence, rather, took on extra duties in overstretched hospital with very little supervision.

And since when was gross negligence manslaughter law the right way to deal with errors made by doctors in training?

Why not corporate manslaughter case against trust?

Concern about reflective notes being used in court – despite being confidential? Used in support of Dr Bawa-Garba to show remediation efforts.

Twitter response from consultants was to emphasise “WE are responsible – so long as you tell us what’s going on”.

Subsequently 2 reviews –

  • Marx review by GMC
  • Williams review by government into medical gross negligence.
    • Suggested that GMC lose right to appeal Tribunal decisions.  Most of these appeals have been regarding sexual misconduct cases.  Professional standards Authority would still be able to appeal.
    • Suggested that GMC not be allowed to access reflective notes eg portfolio.  Could still be used as evidence in prosecution, however, not clear whether would help defence or prosecution more
    • Touched on high rate of cases involving black or minority ethnic doctors, but did nothing other than suggest BAME representation in investigations
    • Recommends explanatory note for gross negligence law, to improve consistency.  Law remains the same, however

Insurance and genetic testing

Ethics, Generic

You have to answer truthfully any question you are asked when applying for insurance.  You do not need to volunteer information not asked for!

The Government and the ABI have a policy framework (‘Concordat’) for cooperation that includes a voluntary Moratorium on insurers’ use of predictive genetic test results (NOT diagnostic tests) until 1 November 2019, (to be reviewed in 2016).  So for most tests, companies cannot force test before providing cover, customers do not need to disclose result while insurance in place, and do not need to disclose results of blood relatives.

Only one exception currently, for cover above £500 000 and Huntingdons.  Certainly no need for time limited policies eg travel, private medical care; really just for life insurance, critical illness and income protection. Recognition that increased risks of a small minority can be mitigated by larger population of policies [2014]  Evidence from US is that significant proportion conceal their diagnosis.

Asymmetry of information—when the customer knows more than the insurer—is the industry’s nightmare.  Testing positive for ApoE4, a mutation of a gene related to increased risk of Alzheimer’s, would be a good reason to get life insurance before symptoms develop.

See also ethics.

Prevention of allergy and autoimmune disease

Allergy, General paediatrics, Immunology

See also asthma prevention.

Immune system starts development in the first trimester, in the womb. Some parts (eg IFN gamma) are constrained, probably to protect the placenta. Immunoglobulin (particular A) still developing through early years – airway mucosal dendritic cells still expanding up until puberty.

The major driving force behind postnatal immune development in all mammalian species is microflora of the gastrointestinal tract – “healthy” development requires not just the right balance of microflora, but also at a crucial window in time.

The hygiene hypothesis (David Strachan) has now been modified to include “old friends” (Graham Rook, talking about microbes that have co-evolved with humans) and finally the biodiversity hypothesis.

So lifestyle becomes important – time spent outdoors, time spent in contact with natural habitats, having diverse, unprocessed diets. Fresh fruit and vegetables have their own microbiome, for instance. And these things are heavily linked to socioeconomic status, particularly housing and green space. Role of artificial sweeteners, emulsifiers, plasticisers and other waste organic compounds?

Mode of birth/delivery affects neonatal colonisation (elective vs emergency section or vaginal) – although so far maternal-infant microbial seeding studies have failed to demonstrate health benefits.

More than 20 studies of probiotics and prevention of allergy.  No safety concerns.  15 found supplementation during pregnancy and lactation may reduce eczema, but no effect in asthma, food allergy, rhinitis.

Fish oil (omega-3) supplementation during pregnancy may reduce risk of allergic sensitisation to egg.

Cochrane 2013 review of prebiotics concluded “promising results in high risk populations”, WAO find in favour (probiotics too), but others institutions have not!

Other dietary exposures, including maternal allergenic food avoidance, vitamin, mineral, fruit and vegetable intake did not appear to influence risk of allergic or autoimmune disease.

There is limited evidence to suggest that supporting mothers to breastfeed for longer reduces risk of eczema in the first year. Longer exclusive breastfeeding duration reduces risk of type 1 diabetes.

EAACI have recommended hypoallergenic formula (“one with documented preventive effect”) for 4/12  (Grade I, evidence A-B).  2024 Chinese systematic review found low quality evidence for extremely hydrolysed formula (EHF) reducing risk of cow’s milk allergy [relative risk (RR): 0.62]. Moderate quality evidence for partially hydrolysed (PHF) and EHF reducing risk of eczema in children (even after 2 y – RR: 0.71-0.79). Moderate quality evidence that PHF only reduced risk of wheeze at age 0-2 y compared with CMF (RR: 0.50), but cf with breast milk, both PHF and EHF increased the risk (RR: 1.61 and 64).

[PLoS Med metanalysis 2018]

Sun exposure around time of birth protects against allergy/atopy, according to French study – for one change in interquartile range, sun exposure prenatally had adjusted odds ratio of 0.47 for sensitisation at age 8-9yrs, and 0.32 for asthma. Postnatal effects less strong. Maternal vitamin D supplementation seemed to increase the risk. All the children were from Paris – sun exposure was calculated from meterological data around time of birth, not time spent outdoors. Ethnicity was not reported.  The suggestion is that the mechanism is vitamin D mediated. Previous studies have had mixed results.

Skin

Since eczema commonly precedes food allergy, it is assumed that disruption of the epithelial barrier is the first step in sensitisation (even when a baby is not eating any food) – the “dual allergen exposure” hypothesis. Peanut protein levels in household correlate with peanut sensitisation in high risk babies.

A couple of different skin “endotypes” – protein/ceramide expression, staph aureus abundance – that seem to predict food allergy. Filaggrin mutations are the strongest genetic risk factor for eczema, and the associated disruption in keratinocytes allows for allergens and irritants to penetrate the skin and trigger inflammation. Detergents/pollutants can further disrupt the skin barrier. Low humidity/temperature also affects (autumn/winter births more at risk).

S aureus colonisation is more likely with eczema, and is associated with severity and persistence – it is also associated with reduced tolerance to egg/peanut, and higher IgE milk/egg/peanut.

Cochrane review of emollients as preventive strategy found no evidence of benefit and possibly more infection. Frequent bathing and oil based bath additives increased the risk of eczema. STOP-AD study (ceramide based emollient, first 2 months of life) found reduced eczema incidence at 1yr in high risk infants. Other studies are looking at trilipid rather than petrolatum based emollients.

Japanese study of “proactive topical steroids” at 7-13 weeks of age (including non-affected skin) found 25% reduction in egg allergy but also reduced weight/length! Calcineurin inhibitors may get around the issue of steroid side effects, if safety data in infants becomes available (so far, so good). [Review, 2024]

Angelman syndrome

General paediatrics, Genetics, Neurology

Caused (mostly) by absence of maternal contribution to a region of the 15q chromosome.  Paternal uniparental disomy is one way this can happen, although mostly there is de novo maternal deletion.  The same region is also responsible for Beckwith-Wiedemann syndrome, but this syndrome is the result of a paternal deletion.

Characteristically “happy puppet” –

  • severe speech and language delay
  • learning disability and epilepsy
  • Movement disorder esp ataxia, also tremor, hyperreflexia
  • open mouthed expression, large mandible
  • Excitability, paroxysmal laughter

[https://www.omim.org/clinicalSynopsis/105830]

Hereditary spherocytosis

General paediatrics, Genetics, Haem/Oncology

One of the genetic red blood cell abnormalities that protects against malaria (cf sickle cell), as haemolysis shortens life span and potential for parasite reproduction.

Phenotype (severity) consistent within family, but very different between families. FH may be vague eg splenectomy, jaundice rather than awareness of underlying diagnosis…

Presentation

Anaemia, jaundice and splenomegaly classically. Splenomegaly is usually mild and there is no increased risk of rupture. Neonatal jaundice can be severe but does not predict severe disease! Severe cases (assessed when well, not during crises, only about 5%) can be transfusion dependent in first years of life (erythropoietin helpful) but not usually afterwards.

May present with parvovirus aplastic crisis (not just red cells; white cells and platelets often drop too) – only happens once.

Diagnosis by spherocytes on film, reduced MCV, high reticulocytes (but retics do not go up during aplastic crisis), unconj hyperbilirubinaemia, splenomegaly. There are other causes of spherocytes, and they can be seen in normal neonatal blood films.

Differential is autoimmune haemolytic anaemia, which is associated with acute viral infection (direct Coombs test usually positive). Osmotic fragility test does not distinguish, can be false negative in iron deficiency, and is unreliable in the first few months of life. New EMA dye binding test takes 2 hours and is 92% sensitive. Gene tests don’t add much.

Other problem is gallstones. High reticulocyte count predicts.

Folate probably only necessary for severe cases.

Splenectomy

Most children are asymptomatic, but severe cases can have growth failure, lethargy, heart failure and leg ulcers. Should be delayed until at least 5 yrs, potentially laparascopic and/or partial. Do cholecystectomy at same time if symptomatic. Platelets rise to abnormally high levels after splenectomy, but no apparent increase in thrombosis.

[Arch Dis Child PMID 15321852]

Haemolysis

General paediatrics, Haem/Oncology

ie red cell breakdown.

Intravascular (eg disseminated intravascular coagulation) or Extravascular (eg hypersplenism)?

Immune or non-immune? Do Indirect Coombs (anti-globulin) test.

Differential:

  • disseminated intravascular coagulation – eg sepsis.  Sick! Low platelets, low Hb, abnormal clotting, high inflammatory markers.
  • Hypersplenism eg G6PD deficiency, storage disorders
  • autoimmune haemolysis (see below)
  • Hereditary spherocytosis

Autoimmune

Type of AHA is usually revealed by antibody screen as part of Direct Antiglobulin Test (DAT) – pattern of anti IgG plus anti C3. 

Basically, warm, cold or paroxysmal cold haemoglobinuria.

Can be primary, or associated with autoimmune disease (eg SLE), lymphoproliferative disorder, infection (EBV, mycoplasma), drugs. Big spleen usually suggests secondary.

Warm means haemolysis at body temperature. Cold means triggered by cold exposure – acrocyanosis (even ischaemia) can be a feature.

Titre less important than threshold temperature for activation!

Paroxysmal cold haemoglobinuria – most common autoimmune haemolytic anaemia in under 3 yrs. Post viral. NB normal platelets, no fragments on film cf HUS. It is intravascular however, unlike warm/cold, so no liver/spleen. Donath-Landsteiner antibody. Can be with localised cold exposure eg hands in cold water, even just drinking cold water!  IgG vs P antigen on RBC.  Can be associated with syphilis. Renal failure. Plasma exchange helps.